摘要: 基于分子亞型進行癌癥分類的顛覆式發(fā)展

全球每4個新增癌癥病例中，就有1例是罕見癌癥。盡管關于罕見癌癥的定義目前還沒有形成統(tǒng)一的說法，但它正在引起越來越多的關注。

Rare cancers account for almost a quarter of all new cancers worldwide though there is no universally adopted definition for rare cancers.

以往，癌癥一般是按照其所在部位和組織類型來分類。但今天，以分子亞型對癌癥進行分類已成為新的趨勢。用分子表征方法分類后，往往會使一些常見癌癥被重新歸類為罕見癌癥。

Historically, cancers have been characterized by location and tissue type. Today, however, cancers are increasingly being grouped based on molecular subtypes. This molecular approach to characterization has resulted in the categorization of some common cancers into groups of rare cancers.

基于分子亞型的癌癥分類不僅改變了癌癥的分類方式，也改變了臨床試驗中新療法的研究方式。

對于這一現象，罕見腫瘤領域會因此出現哪些轉變？申辦方在罕見癌癥臨床試驗中可以通過哪些新方法應對這些轉變？在罕見腫瘤領域擁有豐富經驗的全球CRO普米爾醫(yī)藥（Premier Research）對此給出了幾個關鍵見解。

The grouping of cancer-based on molecular subtypes has changed not only how cancer is categorized but also how novel therapies are investigated in clinical trials. In this blog post, we explore the changing rare oncology landscape and novel approaches to rare cancer trials.

罕見腫瘤領域關鍵轉變：向精準醫(yī)療過渡

傳統(tǒng)的癌癥治療方法主要包括手術、放療和化療。遺傳學和分子分析技術的進步，使得為患者進行個性化定制醫(yī)療護理成為新趨勢。如今隨著精準醫(yī)療或個性化醫(yī)療的出現，診療方式可以針對特定的亞型組患者進行完善，而不必遵循以往“一刀切”式的診療模式。

The transition to precision medicine

Traditionally, cancer has been treated by surgery, radiation, and chemotherapy. Advances in genetics and molecular analysis techniques have made more customized patient care possible. Now, with precision or personalized medicine, treatments can be targeted to a subgroup of patients rather than relying on a one-drug-fits-all model.

"廣譜”腫瘤療法代表

隨著我們對腫瘤分子特征的認識不斷深入，腫瘤的靶向治療有了巨大飛躍。與此同時，與腫瘤或組織類型無關的"廣譜”腫瘤療法也有了很大發(fā)展。這些療法并非基于腫瘤的部位或組織類型，而是基于分子特征進行治療。目前，已通過監(jiān)管部門批準的3種知名"廣譜”腫瘤療法分別為：

? Pembrolizumabin （2017年）-用于高微衛(wèi)星不穩(wěn)定性(MSI-H)或錯配修復缺陷（dMMR）的腫瘤；

? Larotrectinib（2018年）- 用于NTRK基因融合的腫瘤，不同類型癌癥組織學的患者中約0.3%檢測到NTRK基因融合；

? Entrectinib（2019年）- 用于NTRK基因融合的腫瘤。

As our understanding of the molecular characteristics of tumors has improved, there has been a tremendous leap forward not only in targeted therapies but also in the development of tumor-or tissue-agnostic treatments. These therapeutics are based not on tumor location or tissue type but on molecular characterization. To date, three tumor agnostic therapies have received regulatory approval:

? Pembrolizumabin 2017 for tumors with microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR)

? Larotrectinib in 2018 for tumors with NTRK gene fusions, which are found in approximately 0.3 percent of patients with varying cancer histologies

? Entrectinib in 2019 for tumors with NTRK gene fusions

推動腫瘤藥物無縫開發(fā)

在腫瘤學領域，尤其是罕見腫瘤學領域，有越來越多的研究項目已經從傳統(tǒng)藥物開發(fā)途徑過渡到無縫藥物開發(fā)途徑。通過新興的無縫藥物開發(fā)途徑，申辦方可以將藥理學、治療性探索研究和驗證性研究相結合，以實現加速審批的目的（見圖一）。

Pushing the envelope with seamless oncology drug development

In oncology, particularly rare oncology, there are an increasing number of programs that have transitioned from a traditional drug development pathway to a seamless one, where pharmacology, therapeutic exploratory, and confirmatory studies are combined to pursue accelerated approval (see Figure 2).

圖1 傳統(tǒng)腫瘤藥物開發(fā)對比無縫腫瘤藥物開發(fā)

無縫式罕見腫瘤藥物開發(fā)的關鍵挑戰(zhàn)

?患者群體較少

?患者招募困難

?試驗設計因素 - 試驗目標、研究群體、亞型分組，以及療效評估方法等考量因素

?結合基因或生物標記物檢測

?生產商 - 加速審批前提下，生產商將面臨如何滿足營銷新需求的挑戰(zhàn)

Challenges of a seamless approach to drug development in rare oncology include:

? Small populations –

? Access to patients –

? Study design considerations – When preparing to design a rare oncology study, you will need to clearly define the trial objective, the study population and subgroups, and the methodology used to assess response.

? Incorporation of genetic or biomarker testing 

? Manufacturing – With an accelerated program, manufacturing will need to be able to meet the requirements for a marketing application more quickly

由于研發(fā)時間有限，確保臨床、生產、監(jiān)管和營銷規(guī)范之間的一致性，對于通過審批來說也有至關重要的影響。作為一家全球性CRO公司，普米爾醫(yī)藥（Premier Research）提供全方位的產品開發(fā)咨詢和臨床試驗服務，可幫助申辦方優(yōu)化罕見腫瘤藥物的開發(fā)程序。

With shortened timelines, it is also critical to achieve alignment across the clinical, manufacturing, regulatory, and marketing disciplines on how to get to approval. Premier Research offers a full spectrum of product development consulting and clinical development services to help you optimize your rare oncology drug development.

關于普米爾醫(yī)藥（Premier Research）

普米爾醫(yī)藥（Premier Research）是一家臨床研究服務提供商，致力于幫助生物科技、專業(yè)制藥和醫(yī)療器械公司將創(chuàng)新理念和突破性科學成果轉化為新型醫(yī)學療法。無論是制定產品開發(fā)戰(zhàn)略，縮短臨床開發(fā)周期，確保受試者接觸渠道，提供全球法規(guī)咨詢，還是提供罕見腫瘤藥物開發(fā)領域等特定治療領域的專業(yè)知識，普米爾醫(yī)藥致力于在各類醫(yī)療條件下，幫助客戶解決臨床上未被滿足的患者需求。公司官網：https://premier-research.com

Premier Research, a clinical research company, is dedicated to helping biotech, specialty pharma, and device innovators transform life-changing ideas and breakthrough science into new medical treatments. Whether it's developing product lifecycle strategies, reducing clinical development cycle times, securing access to patients, navigating global regulations, or providing expertise in specific therapeutic areas（ like tumor-or tissue-agnostic treatments trails ）, Premier Research is committed to helping its customers answer the unmet needs of patients across a broad range of medical conditions.